New sedatives and anticonvulsants



United States Patent NEW SEDATIVES AND ANTICONVULSANTS Joseph N. Spencer, Media, Pa., assignor to Commercial Solvents Corporation, Terre Haute, Ind., a corpora tion of Maryland No Drawing. Application November 25, 1957 Serial No. 698,369

4 Claims. (Cl. 167-65) 2,902,404 Patented Sept. 1, 1959 ated by comparing the anticonvulsant action of the drugs in male, white mice, weighing 18 to 22 g. The compounds being evaluated were dissolved in pyrogen free water or suspended in 10% acacia and the desired dose administered either orally or intraperitoneally. When the compounds were administered intraperitoneally, 100 rags/kg. of Metrazol were given intraperitoneally simultaneously with the test compound. In the oral studies, 100 mgs./ kg. of Metrazol were given intraperitoneally minutes after the compound. All mice were observed one hour for convulsions and 18-24 hours for death. Five mice were employed at each level and a maximum dose of 500 mgs/kg. was used. Compounds incapable of preventing Metrazol convulsions at this level were considered too inactive to warrant additional studies. Table I below gives the results of convulsant studies on my new relaxants and compares them with the previously known relaxant Tridione and myanesin. The upper row of figures following each compound represents results from oral administration, and the lower row intraperitoneal administration.

Table I LDso, ACDso, ALDso, LDWI LDM mg./kg. mg./kg mg./kg .AODw ALDm -w pr -p p 3;; 1 py fi-P p ij 2 &2 p 1, 020:1:112 325:l;63 US$28 2.8 5.7 2 f 2 methyl 1 Pmpanol 800=b121 175fl=33 ss22 4. e 9. 3 2-n 1tro-Zmethyl-l-butanol 8205578 205510 142530 4. 0 5.8 Trldm e I 1, 3603:96 380:1:48 122:1:31 3. 6 11. 1 Myanesm-B-(o-t0loxy)-1,2-propaned1o1 6105:10 7. 6

ACD =Anticonvulsant dose.

ALD =Anti1ethal dose.

AODso relaxant, ataraxic or antiphobic drugs depending upon the particular form of mental ailment for which they have been found to be most suitable.

The relaxant drugs ordinarily produce reversible paralysis of the voluntary muscles without significantly affecting autonomic functions. One of the most widely used drugs of this type at the present time is Z-methyl-Z-npropyl-1,3-propanediol dicarbamate, generally known as meprobamate. Like most drugs, however, meprobamate is not equally effective with all patients and it produces undesirable side etfects in many cases including such unfavorable efiects as cutaneous, muscular, gastrointestinal, and paradoxical cerebral efiects. The desirability of having available drugs not subject to all or even a portion of these undesirable effects and in general are even more effective as relaxants appears obvious.

I have discovered that the compounds designated by the structural formula amples of such compounds include 2-nitro-2-n-propyl-l,3-

propanediol, 2-nitro-2-isopropyl-1,3-propanediol, 2-nitro- Z-methyl-l-propanol, Z-nitro-Z-methyl-l-butanol, B-nitro- 2-butanol, and 4-nitro-3-hexanol.

My new sedative and anticonvulsant drugs were evalu- Table II shows the duration of anticonvulsant activity of my new relaxants in mice.

1 Control mice given Metrazol simultaneously with 300 rug/kg. of this compound had typical Metrazol convulsions 821- minutes after Metrazol was administered.

Certain of my compounds were tested by the method of E. A. Swinyard (J. Am. Pharm. Ass0c., scientific ed., 38, 201, (1949)), to determine the electroshock convulsive threshold of mice determined by using a stimulus delivered from an electroshock apparatus. The mice were stimulated with a small rat electrode placed on the parietal lobes just behind the eyes. They were restrained only by the hand and released immediately after a stimulation lasting 0.2 second. The compound tested was dissolved in water and 300 rug/kg. administered intraperitoneally to the test animal. Twenty minutes after administration of the compound maximal electroshock seizure (MES) and normal electroshock threshold (NET) tests were made. The end point for MES tests was abolition of the extension of the hind legs during the tonic phase of the seizure when a stimulus five times the threshold was employed. Absence of facial clonus for a period of 10 seconds following stimulation with a shock 20% greater thanthreshold was taken as the end point for the NET tests.

' 'Table III below gives results for certain of my compounds tested in this manner.

Toxie doses. 1 2 At 200 mg.lkg.

Table IV below shows a comparison of certain of my compounds with the relaxant meprobamate. In each case the 'compoundwas administered orally 'to the test animals (mice) and the time of reaction determined. The values are in minutes except where otherwise indicated.

Now having described my invention what I claim is: 1'. A composition in unit dosage form for use in producing ataraxia containing as the essential active ingredient 0.25-0.5 g. of a compound having the structural formula:

N R J-R 1% Where R is hydrogen, methyl, ethyl, n-propyl, and isopropyl, R is hydroxymethyl, l-hydroxyethyl, and l-hydroxypropyl, and R is methyl, ethyl and hydroxymethyl.

2. A composition in unit dosage form for use in producing ataraxia containing as the essential active ingredient 0.25-0.5 g. of 2-nitro-2-propyl-1,3-propanediol. 3. The process of effecting ataraxic efiects in the living human body which comprises administering a compound having the structural formula:

R OR l where R is hydrogen, methyl, ethyl, n-propyl, and isopropyl, R is 'hydroxymethyl, l-hydroxyethyl, and l-hydroxyp'ropyl, and R is methyl, ethyl and hydroxymethyl.

Table IV 2-methy1-2-n-propy1-1,3- 2-nitro-2-n-propyl-1,3- 4-n1tro-3- propanediol (meprobamate) propanediol dicarbamate hexanol 1,600 800 400 1,600 800 V 400 400 nag/kg mg./kg. mgJkg. mg./kg. rug/kg. mg./kg. rug/kg.

Time of first evidence of disturb- 2- 2- 3- 1 2 2.

ance. Time of greatest depression 7 10 3.; 6 18 2. Time of hypnosis 12 20 none 7 15 none... none. Time of catalepsy none none 30 none. none.. none. Time of onset of recovery 4 hrs 2 hrs 1% hrs 4% hrs- 1% hrs-- 1 hr 30. Time of complete recovery 8 hrs 5% hrs" 2 hrs 8 hrs-. 5 hrs 2 hrs 2 hrs.

I am aware of the fact that certain substituted diols and dicarbamates of substituted diols possess central depressant properties. I have now discovered, however, that the introduction of the N0 group into substituted diols gives central nervous system depressants of equal and in some cases decidedly higher eiiectiveness than previously known drugs of this type and which possess the additional advantage of being relatively free from the concomitant depression or anesthesia generally induced by previously available drugs of this class.

The results with animals shown in the tables above have been confirmed by clinical use in man. One to two 0.25 g. doses administered four times daily produced a generally tranquilizing effect and in some patients an hypnotic effect as well.

My new sedatives and anticonvulsants are preferably administered orally in the form of tablets, capsules or other suitable forms. Preferred doses range from 0.25 to 0.50 gm., two to four times daily, or single doses of 0.5 to 1.0 gm. daily.

4. A process of effecting ataraxic effects in the living human body which comprises administering in oral unit dosage form 2-nitro 2-propyl-l,3-propanediol in amounts ranging from 1.0 g. to 2.0 g; per day.

:References Cited in the file of'this patent UNITED STATES PATENTS Vanderbilt Oct. 4, 1938 Bass et al. Dec. 6, 1938 OTHER REFERENCES Brit. Med. 1., Mar. 22, 1958, pp.

UNITED STATES PATENT; OFFICE CERTIFICATE OF CORRECTION Patent No. 2,902,404 September 1 1959 Joseph N, Spencer It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Columns 3. and 4, Table IV, the heading over columns 2, 1, and 4 thereof, for 2methyl2-n-propyll 3&propanedi0l (mepr0bamate)" read 2-methyl-2n- -propyl-l, 3-propanediol dicarbamate (meprobamate) same columns 3 and 4 Table IV the heading over columns 5, 6 and 7 thereof for "'.2nitro2 n-pr0pyll,;3propanediol dicarbamate'? read 2-nitro2-n-- propyll,3propanediol Signed and sealed this 9th day of August 1960.,

(SEAL) Attest:

KARL H AXLINE ROBERT C. WATSON Attesting Officer Commissioner of Patents 

1. A COMPOSITION IN UNIT DOSAGE FORM FOR USE IN PRODUCING ATARAXIA CONTAINING AS THE ESSENTIAL ACTIVE INGREDIENT 0.25-0.5 G. OF A COMPOUND HAVING THE STRUCTURAL FORMULA: 